Unique cellular events occurring during the initial interaction of macrophages with matrix-retained or methylated aggregated low density lipoprotein (LDL) - Prolonged cell-surface contact during which LDL-cholesteryl ester hydrolysis exceeds LDL protein degradation

A critical event in atherogenesis is the interaction of arterial wall macro phages with subendothelial lipoproteins, Although most studies have investi gated this interaction by incubating cultured macrophages with monomeric li poproteins dissolved in media, arterial wall macrophages encounter lipoprot eins that are mostly bound to subendothelial extracellular matrix, and thes e lipoproteins are often aggregated or fused. Herein, we utilize a speciali zed cell-culture system to study the initial interaction of macrophages wit h aggregated low density lipoprotein (LDL) bound to extracellular matrix. T he aggregated LDL remains extracellular for a relatively prolonged period o f time and becomes lodged in invaginations in the surface of the macrophage s. As expected, the degradation of the protein moiety of the LDL was very s low. Remarkably, however, hydrolysis of the cholesteryl ester (CE) moiety o f the LDL was 3-7-fold higher than that of the protein moiety, in stark con trast to the situation with receptor-mediated endocytosis of acetyl-LDL, Si milar results were obtained using another experimental system in which the degradation of aggregated LDL protein was delayed by LDL methylation rather than by retention on matrix. Additional experiments indicated the followin g properties of this interaction: Co) LDL-CE hydrolysis is catalyzed by lys osomal acid lipase; (b) neither scavenger receptors nor the LDL receptor ap pear necessary for the excess LDL-CE hydrolysis; and Cc) LDL-CE hydrolysis in this system is resistant to cellular potassium depletion, which further distinguishes this process from receptor-mediated endocytosis. In summary, experimental systems specifically designed to mimic the in vivo interaction of arterial wall macrophages with subendothelial Lipoproteins have demonst rated an initial period of prolonged cell-surface contact in which CE hydro lysis exceeds protein degradation.